Cell surface–anchored serine proteases in cancer progression and metastasis

Martin, Carly; List, Karin

doi:10.1007/s10555-019-09811-7

Cited by 88 publications

(103 citation statements)

References 201 publications

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“…Excess matriptase activity also leads to the disturbance of epithelial integrity in the intestine . Moreover, matriptase is known to be upregulated in various human cancers and deregulated activities of matriptase contribute to tumor progression . In colorectal cancers, the ratio of matriptase / HAI‐1 mRNA is increased during the early stages of carcinogenesis .…”

Section: Discussionmentioning

confidence: 99%

Protease‐activated receptor‐2 accelerates intestinal tumor formation through activation of nuclear factor‐κB signaling and tumor angiogenesis in Apc^Min/+ mice

et al. 2020

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Hepatocyte growth factor activator inhibitor‐1 (HAI‐1), encoded by the SPINT1 gene, is a membrane‐bound protease inhibitor expressed on the surface of epithelial cells. Hepatocyte growth factor activator inhibitor‐1 regulates type II transmembrane serine proteases that activate protease‐activated receptor‐2 (PAR‐2). We previously reported that deletion of Spint1 in ApcMin/+ mice resulted in accelerated formation of intestinal tumors, possibly through enhanced nuclear factor‐κB signaling. In this study, we examined the role of PAR‐2 in accelerating tumor formation in the ApcMin/+ model in the presence or absence of Spint1. We observed that knockout of the F2rl1 gene, encoding PAR‐2, not only eliminated the enhanced formation of intestinal tumors caused by Spint1 deletion, but also reduced tumor formation in the presence of Spint1. Exacerbation of anemia and weight loss associated with HAI‐1 deficiency was also normalized by compound deficiency of PAR‐2. Mechanistically, signaling triggered by deregulated protease activities increased nuclear translocation of RelA/p65, vascular endothelial growth factor expression, and vascular density in ApcMin/+‐induced intestinal tumors. These results suggest that serine proteases promote intestinal carcinogenesis through activation of PAR‐2, and that HAI‐1 plays a critical tumor suppressor role as an inhibitor of matriptase, kallikreins, and other PAR‐2 activating proteases.

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Section: Discussionmentioning

confidence: 99%

Protease‐activated receptor‐2 accelerates intestinal tumor formation through activation of nuclear factor‐κB signaling and tumor angiogenesis in Apc^Min/+ mice

et al. 2020

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“…In the ligand-dependent activation, proteolytic activation of pro-HGF is necessary. As mentioned above, two major activating protease families were reported: 1) a serum serine protease, HGFA; and 2) type II transmembrane serine proteases (TTSPs) such as matriptase, hepsin, and transmembrane protease/serine (TMPRSS) 2 [3,[10][11][12]. Although these pro-HGF activating proteases are tightly regulated by two transmembrane serine protease inhibitors, HAI-1 and HAI-2, downregulation of HAIs has been observed in several cancers and has been shown to induce progression [11,12].…”

Section: Hgf/met and The Related Moleculesmentioning

confidence: 99%

“…Although these pro-HGF activating proteases are tightly regulated by two transmembrane serine protease inhibitors, HAI-1 and HAI-2, downregulation of HAIs has been observed in several cancers and has been shown to induce progression [11,12]. The TTSP family in humans consists of 17 serine proteases [3,10,17]. The structures are specified as a single-pass hydrophobic transmembrane domain near the N-terminus with a short intracellular domain and a large extracellular portion including a carboxy-terminal serine protease domain [3,10,17].…”

Section: Hgf/met and The Related Moleculesmentioning

confidence: 99%

“…Indeed, coagulation cascade is initiated in pericancerous lesion, and then HGFA changes to the active form by thrombin-induced proteolytic activation [3][4][5][6][7]. Subsequently, several cell-surface transmembrane-type activators, including hepsin and matriptase, were identified [8][9][10][11][12]. These proteases may also be candidates for major activators considering HGF behavior (the so-called sticky protein) and the functional location (MET is located on the cell membrane).…”

Section: Introductionmentioning

confidence: 99%

“…In physiological condition, the activation is tightly regulated by specific cell-surface protease inhibitors such as HGFA inhibitors (HAIs). However, dysregulated overactivation of pro-HGF has been reported to aggressively induce cancer invasion and metastasis through increased phosphorylation of MET [10][11][12]. This review focuses on the cell-surface pro-HGF activation system in urological cancers, including prostate cancer (PC), renal cell carcinoma (RCC), and urothelial carcinoma (UC) of bladder, and summarizes its significance in the progression of cancer.…”

Section: Introductionmentioning

confidence: 99%

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Dysregulation of Type II Transmembrane Serine Proteases and Ligand-Dependent Activation of MET in Urological Cancers

Mukai

Yamasaki

Fujisawa

et al. 2020

IJMS

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Unlike in normal epithelium, dysregulated overactivation of various proteases have been reported in cancers. Degradation of pericancerous extracellular matrix leading to cancer cell invasion by matrix metalloproteases is well known evidence. On the other hand, several cell-surface proteases, including type II transmembrane serine proteases (TTSPs), also induce progression through activation of growth factors, protease activating receptors and other proteases. Hepatocyte growth factor (HGF) known as a multifunctional growth factor that upregulates cancer cell motility, invasiveness, proliferative, and anti-apoptotic activities through phosphorylation of MET (a specific receptor of HGF). HGF secreted as inactive zymogen (pro-HGF) from cancer associated stromal fibroblasts, and the proteolytic activation by several TTSPs including matriptase and hepsin is required. The activation is strictly regulated by HGF activator inhibitors (HAIs) in physiological condition. However, downregulation is frequently observed in cancers. Indeed, overactivation of MET by upregulation of matriptase and hepsin accompanied by the downregulation of HAIs in urological cancers (prostate cancer, renal cell carcinoma, and bladder cancer) are also reported, a phenomenon observed in cancer cells with malignant phenotype, and correlated with poor prognosis. In this review, we summarized current reports focusing on TTSPs, HAIs, and MET signaling axis in urological cancers.

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Proteolytic cleavage of Trop2 at Arg87 is mediated by matriptase and regulated by Val194

et al. 2020

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Proteolytic processing is an important post-translational modification affecting protein activity and stability. In the current study, we investigate the N-terminal cleavage of Trop2, a protein which is overexpressed in many cancers. We demonstrate that Trop2 is cleaved at Arg87 by a transmembrane serine protease, matriptase. Homology modeling and site-directed mutagenesis of amino acids in close proximity to the matriptase cleavage site reveal the importance of Val194 in regulating Trop2 cleavage. Co-immunoprecipitation studies confirm that amino acid substitutions at Arg87, Thr88, Lys189, Val194, and His195 do not affect Trop2 dimerization. However, cleavage of wild-type Trop2 by matriptase is inhibited when it is allowed to dimerize with a V 194 A mutant monomer, further confirming the role of Val194 in matriptase-mediated N-terminal cleavage.

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Cell surface–anchored serine proteases in cancer progression and metastasis

Cited by 88 publications

References 201 publications

Protease‐activated receptor‐2 accelerates intestinal tumor formation through activation of nuclear factor‐κB signaling and tumor angiogenesis in Apc^Min/+ mice

Protease‐activated receptor‐2 accelerates intestinal tumor formation through activation of nuclear factor‐κB signaling and tumor angiogenesis in Apc^Min/+ mice

Dysregulation of Type II Transmembrane Serine Proteases and Ligand-Dependent Activation of MET in Urological Cancers

Proteolytic cleavage of Trop2 at Arg87 is mediated by matriptase and regulated by Val194

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Cell surface–anchored serine proteases in cancer progression and metastasis

Cited by 88 publications

References 201 publications

Protease‐activated receptor‐2 accelerates intestinal tumor formation through activation of nuclear factor‐κB signaling and tumor angiogenesis in ApcMin/+ mice

Protease‐activated receptor‐2 accelerates intestinal tumor formation through activation of nuclear factor‐κB signaling and tumor angiogenesis in ApcMin/+ mice

Dysregulation of Type II Transmembrane Serine Proteases and Ligand-Dependent Activation of MET in Urological Cancers

Proteolytic cleavage of Trop2 at Arg87 is mediated by matriptase and regulated by Val194

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Protease‐activated receptor‐2 accelerates intestinal tumor formation through activation of nuclear factor‐κB signaling and tumor angiogenesis in Apc^Min/+ mice

Protease‐activated receptor‐2 accelerates intestinal tumor formation through activation of nuclear factor‐κB signaling and tumor angiogenesis in Apc^Min/+ mice